GASTRIC NEUROENDOCRINE TUMOR: WHEN SURGICAL TREATMENT IS INDICATED?

ABSTRACT BACKGROUND: Gastric neuroendocrine tumors are a heterogeneous group of neoplasms that produce bioactive substances. Their treatment varies according to staging and classification, using endoscopic techniques, open surgery, chemotherapy, radiotherapy, and drugs analogous to somatostatin. AIMS: To identify and review cases of gastric neuroendocrine neoplasia submitted to surgical treatment. METHODS: Review of surgically treated patients from 1983 to 2018. RESULTS: Fifteen patients were included, predominantly female (73.33%), with a mean age of 55.93 years. The most common symptom was epigastric pain (93.3%), and the mean time of symptom onset was 10.07 months. The preoperative upper digestive endoscopy (UDE) indicated a predominance of cases with 0 to 1 lesion (60%), sizing ≥1.5 cm (40%), located in the gastric antrum (53.33%), with ulceration (60%), and Borrmann III (33.33%) classification. The assessment of the surgical specimen indicated a predominance of invasive neuroendocrine tumors (60%), with angiolymphatic invasion in most cases (80%). Immunohistochemistry for chromogranin A was positive in 60% of cases and for synaptophysin in 66.7%, with a predominant Ki-67 index between 0 and 2%. Metastasis was observed in 20% of patients. The surgical procedure most performed was subtotal gastrectomy with Roux-en-Y reconstruction (53.3%). Tumor recurrence occurred in 20% of cases and a new treatment was required in 26.67%. CONCLUSIONS: Gastric neuroendocrine tumors have a low incidence in the general population, and surgical treatment is indicated for advanced lesions. The study of its management gains importance in view of the specificities of each case and the need for adequate conduct to prevent recurrences and complications.


A QUEDA DA PRESSÃO PORTAL APÓS DESVASCULARIZAÇÃO ESOFAGOGÁSTRICA E ESPLENECTOMIA INFLUENCIA A VARIAÇÃO DO CALIBRE DAS VARIZES E AS TAXAS DE RESSANGRAMENTO NA ESQUISTOSSOMOSE NO SEGUIMENTO EM LONGO PRAZO?
Does the drop in portal pressure after esophagogastric devascularization and splenectomy variation of variceal calibers and the rebleeding rates in schistosomiasis in late follow-up?
Walter de Biase SILVA-NETO 1 , Claudemiro QUIRESE 1 , Eduardo Guimarães Horneaux de MOURA 2 , Fabricio Ferreira COELHO 3 , Paulo HERMAN 3 ABSTRACT -Background: The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy.However, studies have shown varices recurrence especially after long-term follow-up.Aim: To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS.Methods: Thirty-six patients submitted to EGDS portal pressure drop, more or less than 30%, and compared with the behavior of esophageal varices and the rate of bleeding recurrence.Results late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy.

Conclusion
variceal calibers when comparing pre-operative and early or late post-operative diameters.
The comparison between the portal pressure drop and the rebleeding rates was also not

Perspectives
The studies on neuroendocrine tumors gain importance given the specificities of each case and the need for adequate management to prevent recurrences and complications.Endoscopic treatment and minimally invasive surgery have gained importance in the management of these tumors, but conventional surgery should still be considered in a significant number of events, especially in the presence of type III and IV tumors.

Central Message
Neuroendocrine tumors are uncommon neoplasms and represent about 0.5% of new cancer cases worldwide.The stomach is the most common site for tumors of this type.The incidence rates of gastric events and other neuroendocrine tumors are on the rise, possibly due to the great detection in endoscopic and histopathological exams.Most gastric cases are endoscopically treated.Surgical treatment is reserved for cases where endoscopic resection cannot be performed or that present poor prognosis factors such as deep invasion and lymph node metastases.
Computed tomography (CT) was performed on 14 patients (93.33%), and liver metastasis was found in three of them (20%).Octreoscan was performed in four cases (26.67%), with liver and bone metastasis detected in one patient (6.67%) and liver and lymph node metastasis in another (6.67%).
Comorbidities and other concomitant diseases are described in Table 1.Patients with arterial hypertension and other cardiovascular diseases predominated (53.33%).Previous smoking was reported in six patients (40%) and alcohol consumption in five (33.33%).
The time of symptoms onset ranged from 0 to 60 months, with a mean of ten months.The most common reported symptom was epigastric pain (93.33%), followed by bloating (46.67%), and weight loss (46.67%).
Surgical procedure was indicated in most cases (80%), for curative purposes.The subtotal gastrectomy with Rouxen-Y reconstruction was the technique most applied (53.33%).In two patients, reconstruction was performed through double transit in modified Rosanov technique 29 (13,33%); one patient underwent total gastrectomy with Roux-en-Y reconstruction; one was submitted only to Roux-en-Y gastroenterostomy due to advanced tumor (6.67%), another underwent lesion resection plus peritoneal implant resection plus liver metastasis resection (6.67%), and another had subtotal esophagectomy plus partial gastrectomy and reconstruction with gastric tube and cervical esophagogastric anastomosis (6.67%).The characteristics of the 15 cases studied, surgical procedures, recurrence, and follow-up time are summarized in Table 3.
The histopathological findings of the biopsies performed by UDE, the histopathological results of the surgical specimens, and the immunohistochemical tests are in Table 4.No neuroendocrine differentiation was found in the biopsy obtained by UDE in eight cases (53.33%), with a predominance of gastric adenocarcinoma INTRODUCTION N euroendocrine tumors (NET) are uncommon neoplasms and represent about 0.5% of new cancer cases 37 .Its incidence ranges from 3.7 to 30% 17 , and the stomach is the most common site of all NETs 30 .The incidence rates of gastric NETs as well as other NETs are on the rise, possibly due to the great detection in endoscopic and histopathological exams 13,36 .
Regarding histomorphological characteristics, gastric NETs can be classified into four main subgroups 26 : Type I: It is the main type of neuroendocrine tumor, responsible for about 70-80% of cases and usually associated with chronic atrophic gastritis.It presents as multiple tumors, ranging from 1 to 2 cm, and with low metastatic potential 22,26 .
Type II: Tumors are histologically similar to type I but differ in that they are associated with Zollinger-Ellison syndrome or multiple endocrine neoplasia syndromes type 1 (MEN-1).These are rare tumors that, like type I, present as multiple small nodules.The metastatic potential is still low, but it is more significant than type I tumors 10,14,26 .
Type III: They are sporadic, single, large lesions with a high infiltrative and metastatic potential, especially in cases of poorly differentiated tumors.Usually, preexisting pathological conditions are not observed, as occurs in type I and II 26,33 .
Type IV: They are rare and present as single, large, poorly differentiated lesions with high infiltrative and metastatic potential.In addition to the characteristics already described, type IV tumors differ from the other subtypes, because they are not associated with cells similar to the enterochromaffin cells.They derive from other endocrine cells, which secrete hormones such as serotonin, gastrin and adrenocorticotropic hormone 26,35 .
In 2017, the WHO proposed a new classification of gastrointestinal NETs.They were divided into well-differentiated neuroendocrine neoplasms, subdivided into G1 neuroendocrine tumor (mitotic index <2%) and G2 (mitotic index between 2 and 20%), and poorly-differentiated neuroendocrine neoplasms, which include the G3 neuroendocrine carcinoma (mitotic index >20%), subdivided into small cell, large cell, and mixed neoplasms 28,38 .
The definitive diagnosis of the lesions is by biopsy, usually performed during upper digestive endoscopy (UDE).It is recommended an immunohistochemical analysis, including analysis of chromogranin A and synaptophysin for diagnosis, and the Ki-67 proliferative index, indicative of prognosis 21,32,36,39 .
Currently, most cases of gastric NET are treated endoscopically.Surgery is reserved for those in which endoscopic resection cannot be performed or that present poor prognosis factors, such as deep invasion and lymph node metastases 4,19,36 .
The objective of the present study was to identify and review the cases of gastric neuroendocrine neoplasia that underwent surgical treatment.

METHODS
The medical records of patients with gastric NETs diagnosed between 1983 and 2018 and treated surgically were reviewed.The study was approved by the Ethics Committee of the State University of Campinas (Unicamp), under CAAE 78447517.0.0000.5404.

RESULTS
The study included 15 patients, of which four (26.67%) were male and 11 (73.33%) were female.Age ranged from 20 to 77 years, with an average of 55.93 years.(46.67%).Of the total patients, seven (46.67%) were positive for chromogranin A and synaptophysin.The Ki-67 index was evaluated in seven cases, with two presenting values between 0 and 2%, four between 3 and 20%, and one >20%.On the other hand, in the analysis of surgical specimens, events of invasive neuroendocrine tumor predominated (60%), there was margin involvement in four cases (26.67%), lymph node invasion in seven (46.67%), neural invasion in six (40%), and angiolymphatic in 12 (80%).The immunohistochemical analysis recorded positive chromogranin A in nine patients (60%), and positive synaptophysin in ten (66.67%).The Ki-67 study was carried out in 11 cases showing a rate between 0 and 2%, two cases between 3 and 20%, and four >20%.
Postoperative hospitalization time ranged from 8 to 30 days, with an average of 14 days.Nine patients had postoperative complications, and the surgical wound infections were the most common (26.67%).One patient had severe pulmonary complications and died (6.67%).
The follow-up time ranged from 1 to 32 years, with a mean of 7.87 years.In the latest follow-up, tomography was performed in 13 cases (86.67%), with liver metastases observed in five patients (33.33%), lymph nodes in two (13.33%),bone metastases in one (6.67%),and peritoneal carcinomatosis in one (6.67%).Octreoscan was performed in five cases (33.33%), showing liver and bone metastases and peritoneal carcinomatosis in one of them (6.67%).During the follow-up period, three patients (20.00%) had tumor recurrence and five (33.33%) were reoperated.Adjuvant treatment with octreotide was performed in two patients (13.33%), chemotherapy in four (26.67%), and combined chemotherapy and radiotherapy in four (26.67%).

DISCUSSION
NETs are rare neoplasms, representing about 2% of gastric tumors 17,37 .The incidence is higher in female patients, over 60 years of age, as observed in this study, due to the hormonal profile 13 , the higher prevalence of atrophic gastritis in women, or associated genetic factors 22 .
The evaluation of comorbidities is essential in the therapeutic decision.In a study by Darbà and Marsà 8 in 2019, arterial hypertension was the main comorbidity presented by patients, corroborating this study.This finding is possibly due to the late age of presentation of both diseases 8 .
The smoking and alcoholism are important risk factors for several neoplasms; their impact on gastric NETs is still uncertain, with weak association or absence 7 .
Gastric NETs present slow growth and are usually nonfunctional, differing from other gastrointestinal tumors 15 .Associated clinical manifestations include abdominal pain, anemia, upper gastrointestinal bleeding, and weight loss.However, a significant number of cases may be asymptomatic 5 .Epigastric pain was the most frequent clinical manifestation, reinforcing the importance of considering this diagnosis in the investigation of symptoms.
The UDE is essential in the diagnosis of gastric NETs, and its findings are variable.Type I and II tumors usually present as multiple nodules in the gastric fundus and body, smaller than 1 to 2 cm.Type III tumors are single lesions, generally larger than 2 cm, located mainly in the gastric antrum and fundus.And type IV tumors generally manifest as multiple small lesions 5,20,31 .In this study, there was a predominance of cases with single lesions, larger than 1.5 cm, and located in the gastric antrum -a profile compatible with type III.
Biopsies and histopathological investigation are also essential for treatment.It is recommended that, in addition to the biopsy of the lesion, a biopsy of the surrounding mucosa should be performed to identify atrophic gastritis, intestinal metaplasia, and hyperplasia 15 .Besides, the immunohistochemical study of chromogranin A and synaptophysin are indispensable markers, considering that the histopathological evaluation can be nonspecific and that false-negative results may occur, with diagnostic doubt about other histological types 5 .
CT and magnetic resonance imaging (MRI) are sufficient for staging in most cases 3 .Scintigraphy with radioactive octreotide (linked to indium-111), also known as Octreoscan, can help expose primary tumors or metastases not detected in conventional imaging tests 3 .
The Octreoscan was not performed in all cases (only in four in the preoperative period and in five in the follow-up).In the preoperative, bone metastasis was identified in one patient and lymph node metastases in another, which were not diagnosed by CT.
Clinical, radiological, as well as histological staging are of great importance in analyzing tumor behavior and determining surgical therapy.The histological grade can be defined by the mitotic rate and/or Ki-67 index, classifying NETs into low-grade tumors (G1), with a Ki-67 index from 0 to 2%; intermediate grade (G2), with a Ki-67 index from 3 to 20%; and high-grade tumors (G3), with a Ki-67 index >20% 16,24 .
In eight cases in this study, the initial diagnosis was gastric adenocarcinoma, without previous evidence of NET.However, in the histopathological evaluation of the surgical specimen, the immunohistochemical examination showed the NETs, predominantly G2 tumors.The difference obtained between the evaluation of the biopsy by UDE and the surgical specimen can be explained by intratumoral heterogeneity, which justifies the need to evaluate more mitotically active areas to minimize evaluation divergences 24 .
Surgery remains the best option for the treatment of gastric NETs 16 .Initially, the therapeutic definition should consider the classification proposed by Rindi et al. 34 , which determines the occurrence of three types of gastric NETs: Type I tumors, with multiple lesions smaller than 1 cm, well-differentiated histology, hypergastrinemia, and association with atrophic gastritis and anemia pernicious; Type II tumors, with clinical and laboratory features similar to type I tumors, differing by their association with Zollinger-Ellison syndrome and multiple endocrine neoplasia type I; Type III tumors, characterized by a single ulcerated lesion and histology ranging from well-differentiated to moderately differentiated; and Type IV tumors, characterized by single and large lesions, poorly differentiated and with a high infiltrative and metastatic potential 26,34 .
Types I and II tumors should be evaluated by size, number of lesions, invasion of the muscularis propria layer, and lymph node metastasis.Tumors smaller than 1 cm, with up to five lesions and without muscle or lymph node invasion can be observed or submitted to endoscopic resection.Surgical treatment is the best option when the invasion of the muscularis propria or serosa is diagnosed, and gastrectomy with lymph node resection is recommended 34 .Gastrectomy with lymphadenectomy is indicated for tumors between 1 and 2 cm; for type I and II tumors larger than 2 cm, with six or more lesions, and with muscle layer invasion or lymph node metastasis; and for types III and IV tumors 12,16,38 .
The surgical technique employed may include local excision with endoscopic resection, local resection, subtotal gastrectomy, and total gastrectomy, among others 11,12,25 .
Type I tumors have low risk of metastases, so conservative treatment is recommended especially in smaller lesions, where endoscopic mucosal resection or endoscopic submucosal dissection should be applied.Antrectomy may be an option, especially in cases of hypergastrinemia or recurrence.Finally, somatostatin analogues, such as octreotide, may be a therapeutic option in inoperable cases or in cases of metastatic disease 12,25 .
In type II tumors, resection of the gastrinoma is the surgical approach of choice, and antrectomy does not have a favorable effect 1 .In types III and IV tumors, the preferred treatment is subtotal or total gastrectomy with D2 lymphadenectomy, as in gastric adenocarcinomas 12,34 .Resectable liver metastases must be surgically treated.Arterial embolization, radioablation, and liver transplantation are indicated when tumors are unresectable.Chemotherapy should be considered in cases of extrahepatic metastases or recurrent symptomatic disease 35,36 .In this study, cases treated with subtotal gastrectomy and Rouxen-Y reconstruction with lymphadenectomy predominated.This profile is mainly due to the definition of a cohort of patients who required surgical treatment and the surgical protocols adopted.
Previous studies showed that patients undergoing a gastrectomy presented pulmonary, anastomotic, and cardiac complications 18 .In this study, only two patients had pulmonary complications and three had anastomotic, predominantly surgical wound infections.Prophylactic measures are important, such as nursing care and antibiotic therapy, as well as new surgical approaches, as minimally invasive surgery, which reduces surgical wound infections and pain 18 .
The follow-up of patients must be individualized, according to tumor type and local guidelines.The recommendation of the National Comprehensive Cancer Network is a clinical history, physical examination, UDE, CT or MRI of the abdomen, and serum chromogranin A every six months, for one to two years, followed by once a year for four years, and biennially up to ten years after surgery 23,36 .
Finally, considering tumor recurrence, we observed, in this study, that 20% of cases had recurrence during follow-up and 33.3% required some reoperation, either due to recurrence or management of complications.Data regarding the recurrence of gastric NETs remain heterogeneous.Studies with type I tumors indicated recurrence in 63.6% and 52% of cases 9 .Lin et al. 27 observed tumor recurrence in 47.5% of cases of gastric neuroendocrine carcinoma 27 .In events of recurrence after endoscopic resections, gastrectomy is indicated, in addition to other therapies such as chemotherapy, radiotherapy, and somatostatin analogues 2,6 .

CONCLUSIONS
Gastric NETs have a low incidence in the general population.However, their study gains importance in view of the specificities of each case and the need for adequate management to prevent recurrences and complications.Although endoscopic treatment and minimally invasive surgery have become relevant in the management of these tumors, conventional surgery should still be considered in a significant number of cases, especially in the presence of type III and IV tumors.

Table 1 -
Clinical characteristics of the 15 patients studied.

Table 2 -
Macroscopic findings of the upper digestive endoscopy of the 15 patients studied.

Table 4 -
Histopathological and immunohistochemical analysis after upper digestive endoscopy and in the surgical specimens of the 15 patients studied.